tbuckley/cabot-search huggingface dataset:
Gut-derived bacterial flagellin induces beta-cell inflammation and dysfunction
Authors: Torsten P.M. Scheithauer, Hilde Herrema, Hongbing Yu, Guido J. Bakker, Maaike Winkelmeijer, Galina Soukhatcheva, Derek Dai, Caixia Ma, Stefan R. Havik, Manon Balvers, Mark Davids, Abraham S. Meijnikman, Ömrüm Aydin, Bert-Jan H. van den Born, Marc G. Besselink, Olivier R. Busch, Maurits de Brauw, Arnold van de Laar, Clara Belzer, Martin Stahl, Willem M. de Vos, Bruce A. Vallance, Max Nieuwdorp, C. Bruce Verchere, Daniël H. van Raalte
Journal: Gut Microbes (2022)

Hyperglycemia and type 2 diabetes (T2D) are caused by failure of pancreatic beta cells. The role of the gut microbiota in T2D has been studied, but causal links remain enigmatic. Obese individuals with or without T2D were included from two independent Dutch cohorts. Human data were translated in vitro and in vivo by using pancreatic islets from C57BL6/J mice and by injecting flagellin into obese mice. Flagellin is part of the bacterial locomotor appendage flagellum, present in gut bacteria including Enterobacteriaceae, which we show to be more abundant in the gut of individuals with T2D. Subsequently, flagellin induces a pro-inflammatory response in pancreatic islets mediated by the Toll-like receptor (TLR)-5 expressed on resident islet macrophages. This inflammatory response is associated with beta-cell dysfunction, characterized by reduced insulin gene expression, impaired proinsulin processing and stress-induced insulin hypersecretion in vitro and in vivo in mice. We postulate that increased systemically disseminated flagellin in T2D is a contributing factor to beta-cell failure in time and represents a novel therapeutic target.
Gender in Nepal’s health sector
Authors: Mahesh Puri, Minakshi Dahal, Sarah Hawkes, Kent Buse
Journal: BMJ (2022)

Gender means different things to different people.At its crux, gender is a construct to bring order to social relationships and institutions, and most often to rationalise and perpetuate the unequal distribution of power.It is a building block in the structure of our social and political systems.Health is no exception.
Mitochondrial respiration is decreased in visceral but not subcutaneous adipose tissue in obese individuals with fatty liver disease
Authors: Kalliopi Pafili, Sabine Kahl, Lucia Mastrototaro, Klaus Strassburger, Dominik Pesta, Christian Herder, Jennifer Pützer, Bedair Dewidar, Mona Hendlinger, Cesare Granata, Nina Saatmann, Aslihan Yavas, Sofiya Gancheva, Geronimo Heilmann, Irene Esposito, Matthias Schlensak, Michael Roden
Journal: Journal of Hepatology (2022)
Diagnosis of paediatric tuberculosis by optically detecting two virulence factors on extracellular vesicles in blood samples
Authors: Wenshu Zheng, Sylvia M. LaCourse, Bofan Song, Dhiraj Kumar Singh, Mayank Khanna, Juan Olivo, Joshua Stern, Jaclyn N. Escudero, Carlos Vergara, Fangfang Zhang, Shaobai Li, Shu Wang, Lisa M. Cranmer, Zhen Huang, Christine M. Bojanowski, Duran Bao, Irene Njuguna, Yating Xiao, Dalton C. Wamalwa, Duc T. Nguyen, Li Yang, Elizabeth Maleche-Obimbo, Nhung Nguyen, Lili Zhang, Ha Phan, Jia Fan, Bo Ning, Chenzhong Li, Christopher J. Lyon, Edward A. Graviss, Grace John-Stewart, Charles D. Mitchell, Alistair J. Ramsay, Deepak Kaushal, Rongguang Liang, Eddy Pérez-Then, Tony Y. Hu
Journal: Nature Biomedical Engineering (2022)

Abstract Sensitive and specific blood-based assays for the detection of pulmonary and extrapulmonary tuberculosis would reduce mortality associated with missed diagnoses, particularly in children. Here we report a nanoparticle-enhanced immunoassay read by dark-field microscopy that detects two Mycobacterium tuberculosis virulence factors (the glycolipid lipoarabinomannan and its carrier protein) on the surface of circulating extracellular vesicles. In a cohort study of 147 hospitalized and severely immunosuppressed children living with HIV, the assay detected 58 of the 78 (74%) cases of paediatric tuberculosis, 48 of the 66 (73%) cases that were missed by microbiological assays, and 8 out of 10 (80%) cases undiagnosed during the study. It also distinguished tuberculosis from latent-tuberculosis infections in non-human primates. We adapted the assay to make it portable and operable by a smartphone. With further development, the assay may facilitate the detection of tuberculosis at the point of care, particularly in resource-limited settings.
Oral administration of sodium bicarbonate can enhance the therapeutic outcome of Doxil® via neutralizing the acidic tumor microenvironment
Authors: Hidenori Ando, Ai Ikeda, Maho Tagami, Nana Cristina Amorim Matsuo, Taro Shimizu, Yu Ishima, Kiyoshi Eshima, Tatsuhiro Ishida
Journal: Journal of Controlled Release (2022)
Super-enhancer hijacking LINC01977 promotes malignancy of early-stage lung adenocarcinoma addicted to the canonical TGF-β/SMAD3 pathway
Authors: Te Zhang, Wenjie Xia, Xuming Song, Qixing Mao, Xing Huang, Bing Chen, Yingkuan Liang, Hui Wang, Yuzhong Chen, Xinnian Yu, Zeyu Zhang, Wenmin Yang, Lin Xu, Gaochao Dong, Feng Jiang
Journal: Journal of Hematology & Oncology (2022)

Abstract Background Lung adenocarcinoma (LUAD) is the leading cause of death worldwide. However, the roles of long noncoding RNAs (lncRNAs) hijacked by super-enhancers (SEs), vital regulatory elements of the epigenome, remain elusive in the progression of LUAD metastasis. Methods SE-associated lncRNA microarrays were used to identify the dysregulated lncRNAs in LUAD. ChIP-seq, Hi-C data analysis, and luciferase reporter assays were utilized to confirm the hijacking of LINC01977 by SE. The functions and mechanisms of LINC01977 in LUAD were explored by a series of in vitro and in vivo assays. Results We found that LINC01977 , a cancer-testis lncRNA, was hijacked by SE, which promoted proliferation and invasion both in vitro and in vivo. LINC01977 interacted with SMAD3 to induce its nuclear transport, which facilitated the interaction between SMAD3 and CBP/P300, thereby regulating the downstream target gene ZEB1. Additionally, SMAD3 up-regulated LINC09177 transcription by simultaneously binding the promoter and SE, which was induced by the infiltration of M2-like tumor-associated macrophages (TAM2), subsequently activating the TGF-β/SMAD3 pathway. Moreover, LINC01977 expression was positively correlated with TAM2 infiltration and SMAD3 expression, especially in early-stage LUAD. Higher chromatin accessibility in the SE region of LINC01977 was observed with high expression of TGF-β. Early-stage LUAD patients with high LIN01977 expression had a shorter disease-free survival. Conclusions TAM2 infiltration induced a rich TGF-β microenvironment, activating SMAD3 to bind the promoter and the SE of LINC01977 , which up-regulated LINC01977 expression. LINC01977 also promoted malignancy via the canonical TGF-β/SMAD3 pathway. LINC01977 hijacked by SE could be a valuable therapeutic target, especially for the treatment of early-stage LUAD.
PDIA3 epitope-driven immune autoreactivity contributes to hepatic damage in type 2 diabetes
Authors: Cristina C. Clement, Jaspreet Osan, Aitziber Buque, Padma P. Nanaware, Yoke-Chen Chang, Giorgio Perino, Madhur Shetty, Takahiro Yamazaki, Wanxia Li Tsai, Aleksandra M. Urbanska, J. Mauricio Calvo-Calle, Shakti Ramsamooj, Shakti Ramsamooj, Diego Vergani, Giorgina Mieli-Vergani, Benedetta Terziroli Beretta-Piccoli, Massimo Gadina, Cristina Montagna, Marcus DaSilva Goncalves, Federica Sallusto, Lorenzo Galluzzi, Rajesh K. Soni, Lawrence J. Stern, Laura Santambrogio
Journal: Science Immunology (2022)

A diet rich in saturated fat and carbohydrates causes low-grade chronic inflammation in several organs, including the liver, ultimately driving nonalcoholic steatohepatitis. In this setting, environment-driven lipotoxicity and glucotoxicity induce liver damage, which promotes dendritic cell activation and generates a major histocompatibility complex class II (MHC-II) immunopeptidome enriched with peptides derived from proteins involved in cellular metabolism, oxidative phosphorylation, and the stress responses. Here, we demonstrated that lipotoxicity and glucotoxicity, as driven by a high-fat and high-fructose (HFHF) diet, promoted MHC-II presentation of nested T and B cell epitopes from protein disulfide isomerase family A member 3 (PDIA3), which is involved in immunogenic cell death. Increased MHC-II presentation of PDIA3 peptides was associated with antigen-specific proliferation of hepatic CD4+ immune infiltrates and isotype switch of anti-PDIA3 antibodies from IgM to IgG3, indicative of cellular and humoral PDIA3 autoreactivity. Passive transfer of PDIA3-specific T cells or PDIA3-specific antibodies also exacerbated hepatocyte death, as determined by increased hepatic transaminases detected in the sera of mice subjected to an HFHF but not control diet. Increased humoral responses to PDIA3 were also observed in patients with chronic inflammatory liver conditions, including autoimmune hepatitis, primary biliary cholangitis, and type 2 diabetes. Together, our data indicated that metabolic insults caused by an HFHF diet elicited liver damage and promoted pathogenic immune autoreactivity driven by T and B cell PDIA3 epitopes.
A Means of Assessing Maximal Oxygen Intake
Authors: Kenneth H. Cooper
Journal: JAMA (1968)

One hundred and fifteen US Air Force male officers and airmen were evaluated on a 12-minute field performance test and on a treadmill maximal-oxygen-consumption test. The correlation of the field-test data with the laboratory-determined oxygen-consumption data was 0.897. The significance of this relationship makes it possible to estimate with considerable accuracy the maximal oxygen consumption from only the results of the 12-minute performance test. This test is readily adaptable to large groups, requires minimum equipment, and appears to be a better indicator of cardiovascular fitness than the more commonly accepted 600-yard run. Because of the high correlation with maximal oxygen consumption, it can be assumed that the 12-minute field performance test is an objective measure of physical fitness reflecting the cardiovascular status of an individual.
Risk of preterm birth, small for gestational age at birth, and stillbirth after covid-19 vaccination during pregnancy: population based retrospective cohort study
Authors: Deshayne B Fell, Sheryll Dimanlig-Cruz, Annette K Regan, Siri E Håberg, Christopher A Gravel, Laura Oakley, Gillian D Alton, Eszter Török, Tavleen Dhinsa, Prakesh S Shah, Kumanan Wilson, Ann E Sprague, Darine El-Chaâr, Mark C Walker, Jon Barrett, Nannette Okun, Sarah A Buchan, Jeffrey C Kwong, Sarah E Wilson, Sandra I Dunn, Shannon E MacDonald, Shelley D Dougan
Journal: BMJ (2022)

Abstract Objective To assess the risk of preterm birth, small for gestational age at birth, and stillbirth after covid-19 vaccination during pregnancy. Design Population based retrospective cohort study. Setting Ontario, Canada, 1 May to 31 December 2021. Participants All liveborn and stillborn infants from pregnancies conceived at least 42 weeks before the end of the study period and with gestational age ≥20 weeks or birth weight ≥500 g. Main outcome measures Using Cox regression, hazard ratios and 95% confidence intervals were estimated for preterm birth before 37 weeks (overall and spontaneous preterm birth), very preterm birth (&lt;32 weeks), small for gestational age at birth (&lt;10th centile), and stillbirth. Vaccination against covid-19 was treated as a time varying exposure in the outcome specific risk window, and propensity score weighting was used to adjust hazard ratios for potential confounding. Results Among 85 162 births, 43 099 (50.6%) occurred in individuals who received one dose or more of a covid-19 vaccine during pregnancy—42 979 (99.7%) received an mRNA vaccine. Vaccination during pregnancy was not associated with any increased risk of overall preterm birth (6.5% among vaccinated v 6.9% among unvaccinated; adjusted hazard ratio 1.02, 95% confidence interval 0.96 to 1.08), spontaneous preterm birth (3.7% v 4.4%; 0.96, 0.90 to 1.03), or very preterm birth (0.59% v 0.89%; 0.80, 0.67 to 0.95). No increase was found in risk of small for gestational age at birth (9.1% v 9.2%; 0.98, 0.93 to 1.03) or stillbirth (0.25% v 0.44%; 0.65, 0.51 to 0.84). Findings were similar by trimester of vaccination, mRNA vaccine product, and number of doses received during pregnancy. Conclusion The findings suggest that vaccination against covid-19 during pregnancy is not associated with a higher risk of preterm birth, small for gestational age at birth, or stillbirth.
When I use a word . . . . Too much healthcare—overdiagnosis
Authors: Jeffrey K Aronson
Journal: BMJ (2022)

“Overdiagnosis” is a term that has been used in different ways in medical publications since at least 1913. It originally meant mistaking the diagnosis, labelling a condition as something other than what it is; “misdiagnosis” would have been a better term. However, in recent years the meaning of “overdiagnosis” has changed. It now encompasses at least two broad categories of diagnosis: first, labelling people with a condition of some sort that would not have caused them harm if left undiscovered; secondly, expanding the definition of a disorder to encompass more individuals, especially by altering the threshold of a diagnostic test at which the diagnosis is made. The National Library of Medicine has recently added “overdiagnosis” to its list of medical subject headings (MeSH), accompanied by a definition that includes these two aspects, with the addition of a third, the medicalisation of ordinary experiences, or the phenomenon known as disease mongering. A simple summary of one of the major outcomes of overdiagnosis comes from the subtitle of a book on overdiagnosis: making people sick in the pursuit of health.
Social and behavioural determinants of syphilis: Modelling based on repeated cross-sectional surveys from 2010 and 2017 among 278,256 men who have sex with men in 31 European countries
Authors: Ana Mendez-Lopez, David Stuckler, Ulrich Marcus, Ford Hickson, Teymur Noori, Robert N. Whittaker, Klaus Jansen, Asuncion Diaz, Lukasz Henszel, Annie Velter, Jan C. Semenza, Axel J. Schmidt
Journal: The Lancet Regional Health - Europe (2022)

Syphilis case notifications among men-who-have-sex-with-men (MSM) have increased markedly over the past two decades in Europe. We tested several potential factors for this resurgence.Self-reported data from two cross-sectional waves of the European MSM Internet Survey (EMIS-2010 and EMIS-2017, N = 278,256 participants living in 31 European countries) were used to fit multivariable hierarchical logistic regression models designed to evaluate potential social, behavioural, and interventional determinants of syphilis diagnosis. Additional multivariable hierarchical negative binomial models investigated determinants of the number of non-steady male condomless anal intercourse (CAI) partners. We tested the hypothesis that more CAI and syphilis-screening are associated with syphilis resurgence, both linked to use of pre-exposure prophylaxis (PrEP).Between 2010 and 2017, incidence of syphilis diagnosis in the previous 12 months rose from 2.33% (95%CI: 2.26-2.40) of respondents reporting a syphilis diagnosis in 2010 compared with 4.54% (95%CI: 4.42-4.66) in 2017. Major factors contributing to syphilis diagnosis were living with diagnosed HIV (adjusted odds ratio (aOR) 2.67, 95%CI: 2.32-3.07), each additional non-steady male CAI partner (aOR 1.01, 95%CI: 1.01-1.01), recency of STI-screening (previous month vs no screening, aOR 25.76, 95%CI: 18.23-36.41), selling sex (aOR 1.45, 95%CI: 1.27-1.65), and PrEP use (aOR 3.02, 95%CI: 2.30-3.96). Living with diagnosed HIV (adjusted incidence rate ratio (aIRR) 3.91, 95%CI: 3.77-4.05), selling sex (aIRR 4.39, 95%CI: 4.19-4.59), and PrEP use (aIRR 5.82, 95%CI: 5.29-6.41) were associated with a higher number of non-steady male CAI partners. The association between PrEP use and increased chance of syphilis diagnosis was mediated by STI-screening recency and number of non-steady male CAI partners, both substantially higher in 2017 compared to 2010.Syphilis cases are concentrated in three MSM population groups: HIV-diagnosed, PrEP users, and sex workers. Behavioural and interventional changes, particularly more non-steady male CAI partners and recency of STI-screening, are major contributing factors for increasing syphilis diagnoses among MSM in Europe.European Centre for Disease Prevention and Control.
Dual RNA-seq reveals a type 6 secretion system-dependent blockage of TNF-α signaling and BicA as a <i>Burkholderia pseudomallei</i> virulence factor important during gastrointestinal infection
Authors: Javier I. Sanchez-Villamil, Daniel Tapia, Nittaya Khakhum, Steven G. Widen, Alfredo G. Torres
Journal: Gut Microbes (2022)

Melioidosis is a disease caused by the Gram-negative bacillus Burkholderia pseudomallei (Bpm), commonly found in soil and water of endemic areas. Naturally acquired human melioidosis infections can result from either exposure through percutaneous inoculation, inhalation, or ingestion of soil-contaminated food or water. Our prior studies recognized Bpm as an effective enteric pathogen, capable of establishing acute or chronic gastrointestinal infections following oral inoculation. However, the specific mechanisms and virulence factors involved in the pathogenesis of Bpm during intestinal infection are unknown. In our current study, we standardized an in vitro intestinal infection model using primary intestinal epithelial cells (IECs) and demonstrated that Bpm requires a functional T6SS for full virulence. Further, we performed dual RNA-seq analysis on Bpm-infected IECs to evaluate differentially expressed host and bacterial genes in the presence or absence of a T6SS. Our results showed a dysregulation in the TNF-α signaling via NF-κB pathway in the absence of the T6SS, with some of the genes involved in inflammatory processes and cell death also affected. Analysis of the bacterial transcriptome identified virulence factors and regulatory proteins playing a role during infection, with association to the T6SS. By using a Bpm transposon mutant library and isogenic mutants, we showed that deletion of the bicA gene, encoding a putative T3SS/T6SS regulator, ablated intracellular survival and plaque formation by Bpm and impacted survival and virulence when using murine models of acute and chronic gastrointestinal infection. Overall, these results highlight the importance of the type 6 secretion system in the gastrointestinal pathogenesis of Bpm.
Correction: CircNEIL3 regulatory loop promotes pancreatic ductal adenocarcinoma progression via miRNA sponging and A-to-IRNA-editing
Authors: Peng Shen, Taoyue Yang, Qun Chen, Hao Yuan, Pengfei Wu, Baobao Cai, Lingdong Meng, Xumin Huang, Jiaye Liu, Yihan Zhang, Weikang Hu, Yi Miao, Zipeng Lu, Kuirong Jiang
Journal: Molecular Cancer (2022)
DPP-4 inhibitors and GLP-1RAs: cardiovascular safety and benefits
Authors: Michael Razavi, Ying-Ying Wei, Xiao-Quan Rao, Ji-Xin Zhong
Journal: Military Medical Research (2022)

Abstract Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors are commonly used treatments for patients with type 2 diabetes mellitus (T2DM). Both anti-diabetic treatments function by playing key modulatory roles in the incretin system. Though these drugs have been deemed effective in treating T2DM, the Food and Drug Administration (FDA) and some members of the scientific community have questioned the safety of these therapeutics relative to important cardiovascular endpoints. As a result, since 2008, the FDA has required all new drugs for glycemic control in T2DM patients to demonstrate cardiovascular safety. The present review article strives to assess the safety and benefits of incretin-based therapy, a new class of antidiabetic drug, on the health of patient cardiovascular systems. In the process, this review will also provide a physiological overview of the incretin system and how key components function in T2DM.
Hemopexin accumulates in kidneys and worsens acute kidney injury by causing hemoglobin deposition and exacerbation of iron toxicity in proximal tubules
Authors: Xiaoming Fan, Xiaolu Zhang, Lijun C. Liu, Shungang Zhang, Cole B. Pelger, Haroon Y. Lughmani, Steven T. Haller, William T. Gunning, Christopher J. Cooper, Rujun Gong, Lance D. Dworkin, Rajesh Gupta
Journal: Kidney International (2022)
Intestinal TLR4 deletion exacerbates acute pancreatitis through gut microbiota dysbiosis and Paneth cells deficiency
Authors: Mei Qi-Xiang, Fu Yang, Huang Ze-Hua, Yin Nuo-Ming, Wang Rui-Long, Xu Bin-Qiang, Fan Jun-Jie, Huang Chun-Lan, Zeng Yue
Journal: Gut Microbes (2022)

Toll-like receptor 4 (TLR4) has been identified as a potentially promising therapeutic target in acute pancreatitis (AP). However, the role of intestinal TLR4 in AP and AP-associated gut injury remains unclear. This study aimed to explore the relationship between intestinal TLR4 and gut microbiota during AP. A mouse AP model was establish by intraperitoneal injection of L-arginine. Pancreatic injury and intestinal barrier function were evaluated in wild-type and intestinal epithelial TLR4 knockout (TLR4ΔIEC) mice. Gut microbiota was analyzed by 16S rRNA sequencing. Quadruple antibiotics were applied to induce microbiota-depleted mice. Differentially expressed genes in gut were detected by RNA sequencing. L. reuteri treatment was carried out in vivo and vitro study. Compared with wild-type mice, AP and AP-associated gut injury were exacerbated in TLR4ΔIEC mice in a gut microbiota-dependent manner. The relative abundance of Lactobacillus and number of Paneth cells remarkably decreased in TLR4ΔIEC mice. The KEGG pathway analysis derived from RNA sequencing suggested that genes affected by intestinal TLR4 deletion were related to the activation of nod-like receptor pathway. Furthermore, L. reuteri treatment could significantly improve the pancreatic and intestinal injury in TLR4ΔIEC mice through promoting Paneth cells in a NOD2-dependent manner. Loss of intestinal epithelial TLR4 exacerbated pancreatic and intestinal damage during AP, which might be attributed to the gut microbiota dysbiosis especially the exhausted Lactobacillus. L. reuteri might maintain intestinal homeostasis and alleviate AP via Paneth cells modulation.Abbreviations: AP Acute pancreatitis, TLR4 Toll-like receptor 4, IL-1β Interleukin-1β, IL-6 Interleukin-6, TNF-α Tumor necrosis factor-α, SIRS Systematic inflammatory response syndrome, LPS Lipopolysaccharides, SPF Specific pathogen-free, ZO-1 Zonula occludens-1, CON Control, H&E Hematoxylin and eosin, FISH Fluorescence in situ hybridization, DAPI 4′,6-diamidino-2-phenylindole, PCoA Principal co-ordinates analysis, SCFA Short chain fatty acid, LEfSe Linear discriminant analysis Effect Size, ANOVA Analysis of variance, F/B Firmicutes/Bacteroidetes, PCA Principal component analysis, NOD2 Nod-like receptor 2, ABX antibiotics, PCNA proliferating cell nuclear antigen